Maleque_1984_J.Pharmacol.Exp.Ther_229_72

The effects of the four N-benzylazaspiro analogs of histrionicotoxin, which are without the two side-chains typical of histrionicotoxin, were studied on the ionic channels of electrically excitable membrane and the nicotinic acetylcholine receptors in frog sartorius muscles. Each analog reversibly blocked the indirectly elicited twitch and potentiated the directly elicited twitch in a concentration-dependent manner. The analogs decreased the amplitude and rate of rise and prolonged the falling phase of the directly elicited action potential and blocked delayed rectification suggesting blockade of sodium and potassium conductances. All of the analogs caused a concentration- and voltage-dependent depression of the peak end-plate current amplitude and induced nonlinearity but no hysteresis or time dependency in the current-voltage relationship. The marked shortening of the time constant of end-plate current decay produced by the analogs was concentration-dependent. The relationship between the time constant of end-plate current decay and membrane potential remained a single exponential function of time despite the marked shortening of the decay phase and loss of voltage dependence. The effect of the analogs on miniature end-plate current was identical to that on end-plate current. Single channel conductance was unaffected by the analogs, but the single channel lifetime was shortened. The marked shortening of the time constant of the end-plate current decay and single channel lifetime plus linear relationship between reciprocal of the time constant of decay and analog concentrations strongly suggest that the analogs interact with the ionic channels of the nicotinic acetylcholine receptor in their open conformation.(ABSTRACT TRUNCATED AT 250 WORDS)